A Japanese family of autosomal dominant cerebral small vessel disease with heterozygous HTRA1 mutation showing dementia, gait disturbance and subarachnoid hemorrhage

Abstract

Homozygous mutations of high temperature requirement A serine peptidase 1 (HTRA1) gene cause an autosomal recessive cerebral small vessel disease, namely cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Meanwhile, heterozygous mutations of the HTRA1 can also cause an autosomal dominant small vessel disease with a milder clinical phenotype. Here we described 2 patients in a Japanese family with the same heterozygous HTRA1 mutation (c.496 C>T, p.R166C), showing a unique clinical history of traumatic subarachnoid hemorrhage (SAH), no alopecia or spondylosis, in addition to previously similar clinical phenotypes such as cognitive impairment, gait disturbance, and hyperreflexia. The present cases suggest that traumatic SAH may be an important risk of the heterozygous HTRA1 mutation (c.496 C>T, p.R166C), especially in Asia.